Chronic Obstructive Pulmonary Disease (COPD) due largely to the inhalation of tobacco smoke is a major cause of morbidity and mortality being the fourth most common cause of death in the World (Lung Disease Data (2008). American Lung Association). According to estimates by the National Heart, Lung and Blood Institute, in 2007, the annual cost in US for COPD was $42.6 billion, including $26.7 million in direct health care (Lung Disease Data (2008). American Lung Association). The failure of established medical therapy to substantially improve outcome has been disappointing and new management strategies are needed (Global Initiative for COPD (2006). Global Strategy for the Diagnosis, Management & Prevention of COPD, which can be found on the web site of the Global Initiative for Chronic Obstructive Lung Disease). The underlying pathology of COPD includes a narrowing of the small airways and destruction of lung parenchyma, outcomes that at least in part are a consequence of an inflammatory process. Recurrent acute exacerbations are linked to worsening of airflow obstruction and health status possibly because they reflect more intense intrabronchial inflammation. The cause of this inflammatory response is complex, but in part includes bacterial colonization of the intrapulmonary bronchus mucosa which has been damaged by inhalation of toxic material (Sethi, 2006, Chest 129:223-224).
Acute exacerbations are critical events in the natural history of COPD and are more common in severe disease. Acute exacerbations reduce quality of life, accelerate further decline in lung function, and are major determinants of hospitalization and death (Global Initiative for COPD, 2006; Niewoehner, 2006, Am. J. Med. 119(10 Suppl. 1):38-45; Wedzicha & Seemungal, 2007, Lancet 370(9589):786-96; Sethi, 2006, Chest 129:223-224; Anzueto, 2007, Clin. Chest Med. 28(3):609-16, vii; and Look et al., 2006, Proc. Am. Thorac. Soc. 3(6):482-3). Once patients are hospitalized with an exacerbation they remain at high risk of hospital readmission or death (Sin & Tu, 2001, Am. J. Respir. Crit. Care Med. 164(4):580-4).
Prevention of COPD exacerbations is a major goal of management (Global Initiative for COPD Guidelines, 2002; Celli & MacNee, 2004, Eur. Respir. J. 23(6):932-46; O'Donnell et al., 2007, Can. Respir J. 14 Suppl. B:5B-32B), with prevention or reduction in the number of exacerbations likely having beneficial effects on the long-term clinical course of the disease and patients' quality of life (Burge et al., 2000, BMJ 320(7245):1297-303; Calverley et al., 2003, Chest 124(4):1350-6; Vincken et al., 2002, Eur. Respir. J. 19(2):209-16; and Casaburi et al., 2002, Eur. Respir J. 19(2):217-24).
Asthma is a chronic inflammatory condition of the airways characterized by reversible airway obstruction, and has traditionally been classified as extrinsic (due to allergic reaction to inhaled allergens such as pollens and house dust mite) or intrinsic (not due to classical allergy), the mechanism for which is unknown. Extrinsic asthma is also referred to as “allergic” asthma, whereas intrinsic asthma is also referred to as “non-allergic” or “idiopathic” asthma.
In contrast to COPD, asthma is a typically chronic condition involving the respiratory system in which the airways occasionally constrict, become inflamed, and are lined with excessive amounts of mucus, often in response to one or more triggers. These episodes may be triggered by such things as exposure to an environmental stimulant such as an allergen, environmental tobacco smoke, cold or warm air, perfume, pet dander, moist air, exercise or exertion, or emotional stress. In children, the most common triggers are viral illnesses such as those that cause the common cold. This airway narrowing causes symptoms such as wheezing, shortness of breath, chest tightness, and coughing. The airway constriction responds to bronchodilators. Between episodes, most patients feel well but can have mild symptoms and they may remain short of breath after exercise for longer periods of time than the unaffected individual. The symptoms of asthma, which can range from mild to life threatening, can usually be controlled with a combination of drugs and environmental changes.
In a recently reported study based on diagnosed asthma subjects, asthma was classified based on differences in eosinophil and neutrophil counts in sputum (Simpson et al., 2006, Respirology 11:54-61). The subjects in the study were divided into different asthma subtypes based on the presence of these cell types compared to healthy control subjects. Several asthma sub-types were identified including neutrophilic asthma (>61% neutrophils) and eosinophilic asthma (>1.01% eosinophils). The neutrophilic asthma group comprised approximately 20% of the overall number of asthmatics. The study further reported persistent neutrophilia in the majority of these subjects over both short term (4 week) and long term (mean 5.3 years) intervals between sampling despite no subject reporting respiratory tract infection during the month prior to assessment. While subjects with asthma were found to have higher levels of intracellular bacteria and macrophages than healthy controls, no significant differences were found between neutrophilic asthmatics and the other asthma groups. Indeed, the levels of bacteria found were stated to be less than that consistent with acute bacterial infections, and the report concluded there was no evidence of bacterial infection to explain the inflammatory process of neutrophilic asthma.
Bronchitis is an inflammation of the bronchi (medium-size airways) in the lungs. Chronic bronchitis (CB) is not necessarily caused by infection and is generally part of COPD syndrome. CB is defined clinically as a persistent cough that produces sputum (phlegm) and mucus, for at least three months in two consecutive years.
Non-typeable Haemophilus influenzae (NTHi) is the most common pathogenic bacteria associated with chronic bronchitis (CB) (Sethi and Murphy, 2001, Clin. Microbiol. Rev. 14:336-363). NTHi can be found in the upper airways (e.g., nose, middle ear, throat and sinuses) of healthy patients and patients with CB (Sethi and Murphy, 2001, Clin. Microbiol. Rev. 14:336-363) as well as several locations of the respiratory tract, including the lumen, adhering to mucosal epithelial cells in the interstitium of the submucosa (Moller et al., 1998, Am. J. Respir. Crit. Care Med. 157:950-56). Studies of non-obstructive and obstructive CB have observed that a large proportion of patients have persistent infection with NTHi (Murphy et al., 2004, Am. J. Respir. Crit. Care Med. 170:266-72).
FIG. 4 is a side perspective view of the rim cover of FIG. 1 engaged with the rim of a wheel, the view is of the side of the wheel adjacent the vehicle;
Both NTHi and Staphylococcus aureus have previously been shown to induce non IgE mediated and enhanced IgE-mediated histamine release from mast cells obtained by broncheoalveolar lavage from the airways of patients with CB. In the case of NTHi, it has been reported that exotoxin may be responsible for the enhancement of IgE mediated histamine release (Clementsen et al., 1990, Allergy 45: 10-17) Immune cells isolated from patients with CB during acute exacerbations have been shown to be both sensitized and hyperactive to the patient's own bacteria (Norn et al., 1994, Agents Actions 41, Special Conference Issue 1994:C22-C23). Several studies have also reported specific IgE antibodies produced in response to respiratory infection by fungi (e.g., Aspergillus) and viruses (e.g., respiratory syncytial virus, parainfluenza virus (Welliver et al., 1982, J. Pediatrics 101:889-96)) and bacteria (S. pneumoniae (Kjaergard et al., 1996, APMIS 104:61-67; Tee and Pepys, 1982, Clin. Allergy 12:439-50; Pauwels et al., 1980, Allergy 157:665-9), S. aureus (Rhode et al., 2004, Respir. Med. 98:858-64; Tee and Pepys, 1982, Clin. Allergy 12:439-50), Pseudomonas aeruginosa (Shen et al., 1981, Infect. Immun. 32:967-68), and Mycoplasma pneumoniae (Seggev et al., 1996, Ann. Allergy Asthma Immunol. 77:67-73). IgE antibodies specific for NTHi have also been identified in the serum of patients with CB (Kjaergard et al., 1996, APMIS 104; 61-67; Tee and Pepys, 1982, Clin. Allergy 12:439-50) and cystic fibrosis (Tee and Pepys, 1982, Clin. Allergy 12:439-50).
In a study of patients with bronchial asthma, IgE antibodies to NTHi were found in 29% of patients. Antibodies to NTHi and/or Streptococcus pneumoniae were also present in 22% of patients with no other IgE mediated hypersensitivity. However, higher levels of IgE bacterial antibodies were found in patients with demonstrable IgE antibodies to various inhalant antigens (suggesting an allergic phenotype) (Pauwels et al., 1980, Allergy 157:665-9). While it has been hypothesized that bacterial infections may play a role in the induction and exacerbation of extrinsic asthma, it has been considered that exacerbation of asthma is predominantly triggered by viral infection. Indeed, the clinical effect of bacterial vaccines in the treatment of asthma has been questioned, leading to international World Health Organization (WHO) recommendations that bacterial vaccines have no role in modern asthma treatment.
Despite massive amounts of research focused on therapeutic asthma intervention and treatment, the condition remains a major, costly and growing problem in modern Westernized societies.
Citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present application.